Structural basis for acyl-group discrimination by human Gcn5L2.
Structural basis for acyl-group discrimination by human Gcn5L2.
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人类GCN5L2抗酰基组歧视的结构基础。
DOI：
10.1107/s2059798316007907
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发表时间：
2016-07
期刊：
影响因子：
--
通讯作者：
Wolberger C
中科院分区：
文献类型：
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作者：
Ringel AE;Wolberger C
结合到丙酰辅酶A和丁酰辅酶A的人Gcn 5L 2的结构显示了活性位点如何适应不同的酰基修饰，并解释了为什么丁酰辅酶A作为竞争性抑制剂。Gcn 5是一种保守的乙酰转移酶，通过乙酰化组蛋白的N-末端尾部来调节转录。最近的研究发现，在体内赖氨酸酰基修饰的化学多样性阵列的动机，乙酰转移酶人Gcn 5（Gcn 5L 2）的酰基链特异性进行了检查。而Gcn 5L 2稳健地催化赖氨酸乙酰化，Gcn 5L 2的酰基转移酶活性随着酰基链长度的增加而逐渐变弱。为了理解Gcn 5如何区分不同的酰基-CoA分子，确定了与丙酰-CoA和丁酰-CoA结合的人Gcn 5L 2的催化结构域的结构。虽然Gcn 5L 2的活性位点可以容纳丙酰-CoA和丁酰-CoA而没有主要的结构重排，但丁酰-CoA采用与催化不相容的构象，这阻碍了进入的赖氨酸残基的路径，并作为Gcn 5L 2相对于乙酰-CoA的竞争性抑制剂。这些结构证明了Gcn 5L 2如何区分酰基链供体，并解释了为什么Gcn 5L 2对大于乙酰基的酰基部分具有弱活性。
Structures of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA show how the active site accommodates different acyl modifications and explain why butyryl-CoA acts as a competitive inhibitor. Gcn5 is a conserved acetyltransferase that regulates transcription by acetylating the N-terminal tails of histones. Motivated by recent studies identifying a chemically diverse array of lysine acyl modifications in vivo, the acyl-chain specificity of the acetyltransferase human Gcn5 (Gcn5L2) was examined. Whereas Gcn5L2 robustly catalyzes lysine acetylation, the acyltransferase activity of Gcn5L2 becomes progressively weaker with increasing acyl-chain length. To understand how Gcn5 discriminates between different acyl-CoA molecules, structures of the catalytic domain of human Gcn5L2 bound to propionyl-CoA and butyryl-CoA were determined. Although the active site of Gcn5L2 can accommodate propionyl-CoA and butyryl-CoA without major structural rearrangements, butyryl-CoA adopts a conformation incompatible with catalysis that obstructs the path of the incoming lysine residue and acts as a competitive inhibitor of Gcn5L2 versus acetyl-CoA. These structures demonstrate how Gcn5L2 discriminates between acyl-chain donors and explain why Gcn5L2 has weak activity for acyl moieties that are larger than an acetyl group.